Drug-drug Interactions Dr. Alia Shatanawi 10-10-2013

Drug-drug interaction When two drugs taken together, there is a possibility that the drugs will interact with each other to cause unanticipated effect. Usually increase or decrease in the desired therapeutic effect. Drug-drug interaction can occur in the following sites 1. at the side of absorption, tetracycline is not absorbed from the GI tract if calcium product present in the stomach. 2. At the site of action, drug antagonism. ex. amino acid and levodopa compete to bind in the same site of the intestine in order to absorb them) Another example –tetracycline drug is not absorbed from the GI tract if calcium product is present in the stomach. Since Tetracyclines chelate di- and trivalent metal ions, forming insoluble complexes, absorption is decreased in the presence of milk, certain antacids and iron preparations.  

Drug-drug interaction During distribution, aspirin competes with methotrexate for protein binding sites, and because aspirin is more competitive for the sites, resulting in increased release of methotrexate and so increase toxicity to tissues. During metabolism (CYP 450). During excretion, digoxin and quinidine are both excreted from the same sites in the kidney. The quinidine will be excreted first because it is more competitive for these sites, resulting in increased serum levels of digoxin.

Adverse effect Adverse effect are undesired effect that may be unpleasant or even dangerous They can occur for many reasons: The drug may have other effects on the body besides the therapeutic effect. The patient is sensitive to the drug. The patient is taking too much or too little of the drug.

Adverse effect With every drug use, unwanted effects must be taken into account. Before prescribing a drug, the physician should therefore assess the risk : benefit ratio.

Adverse Drug Reaction Adverse drug reactions are classified as predictable or unpredictable. A predictable drug reaction is related to the pharmacological actions of the drug. An unpredictable reaction is related to immunological response ( hypersensitivity reactions ) or nonimmunological response

Drug Allergy It is defined as an adverse reaction to a drug by a specific immune response either directly to the drug or one or more of its metabolites alone, or to a drug bound to a body protein such as albumin. Such binding alters the structure of the protein drug/protein complex, rendering it antigenic.

Classification of Allergic Reactions Type Mechanism Time Example I Anaphylactic sec/min Angioedema II Cytotoxic -- Transfusion rx III Immune 6-8hrs Serum sickness complex IV Cell mediated 48 hrs Contact dermatitis

Most Common in Dental Office Type I  Immediate Localized or Generalized Anaphylaxis - The Type I allergic reaction is subdivided into several forms based upon the response Type IV Contact Dermatits

The most common drug to cause allergy Analgesics, such as codeine, morphine, nonsteroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen or indomethacin), and aspirin Antibiotics such as penicillin, sulfa drugs, and tetracycline.

Variation in drug responses Age Body composition Gender Pathophysiology Tolerance Genetics Variability in absorption – bioavailability – oral – ability to reach circulation Compliance

Impact of pregnancy on maternal pharmacodynamics ? GI absorption Reduction in gastric motility Reduction in gastric acid secretions Increases in gastric pH N/V of pregnancy Resultant decrease in a absorption and relative lower plasma drug concentrations

Placental-fetal unit and fetal pharmacology Major route of placental drug transfer is simple diffusion (Concentration gradient) Lipophilic drugs cross more readily Nonionized drugs at the physiologic pH more rapidly Placental blood flow most critical rate-limiting step

pH Fetal pH is slightly more acidic than maternal Weak bases cross the placenta easily When contact occurs with fetal blood, the drug becomes more ‘ionized’- ion trapping Salicylates and valproic acid conc. in the fetus are higher than in the mom

Adults >65 years old Fastest growing population in US 20% of hospitalizations for those >65 are due to medications they’re taking Oxidative metabolism through cytochrome P450 system does decrease with aging, resulting in a decresed clearance of drugs

Pharmacokinetics Decrease in total body water (due to decrease in muscle mass) and increase in total body fat affects volume of distribution Water soluble drugs: lithium, aminoglycosides, alcohol, digoxin Serum levels may go up due to decreased volume of distribution Fat soluble: diazepam, thiopental, trazadone Half life increased with increase in body fat

Pharmacokinetics: Excretion and Elimination GFR generally declines with aging, but is extremely variable 30% have little change 30% have moderate decrease 30% have severe decrease Serum creatinine is an unreliable Marker If accuracy needed, do Cr Cl

Example: Creatinine Clearance vs. Age 30 1.1 90 41 70 53 50 65 CrCl Scr Age

Pharmacodynamics (PD) Definition: the time course and intensity of pharmacologic effect of a drug Age-related changes:  sensitivity to sedation and psychomotor impairment with benzodiazepines  level and duration of pain relief with narcotic agents  drowsiness and lateral sway with alcohol  HR response to beta-blockers  sensitivity to anti-cholinergic agents  cardiac sensitivity to digoxin

Factors contributing to adverse drug reactions in elderly patients Heart, kidney, liver, thyroid Orthostatic hypotension, when they standup, blood goes to their feet - weak sympathetic nervous system response to constrict veins and increase heart rate. Low thyroid function causes lower body temperature, metabolic rate, & heart rate. How many prescription medications are too many? >4 or >6 Many elderly people receive 12 medications per day Polypharmacy

Pediatric Dosing Traditionally, for less frequently used drugs, extrapolation is done from adult dose on a weight or surface area basis Problems • Absorption may be more or less than adult • Clearance of some drugs in children is affected by maturation, as well as size – Cytochrome P450 enzyme system matures over time – Glomerular filtration changes over time “Children are not Small Adults”

CYP isoforms vary with age CYP Enzymes CYP isoforms vary with age For example, clearance of midazolam by CYP 3A4 and 3A5 goes from 1.2 ml/min/kg to 9 ml/min/kg over first few months of life Carbamezapine (3A4) clearance faster in children than adults – requires higher doses